The present invention is directed to biguanide/quaternary ammonium compounds having antimicrobial activity, and to the use of these compounds in pharmaceutical compositions. More specifically, the invention is directed to use of the subject biguanide/quaternary ammonium compounds in compositions and methods for disinfecting contact lenses, and to the use of these compounds to preserve various types of pharmaceutical compositions from microbial contamination, particularly ophthalmic, otic and nasal pharmaceutical compositions.
Contact lenses are exposed to a broad spectrum of microbes during normal wear and become soiled relatively quickly. Routine cleaning and disinfecting of the lenses are therefore required. Although the frequency of cleaning and disinfecting may vary somewhat among different types of lenses and lens care regimens, daily cleaning and disinfecting is normally required. Failure to clean and disinfect the lens properly can lead to a multitude of problems ranging from mere discomfort when the lenses are being worn to serious ocular infections. Ocular infections caused by particularly virulent microbes, such as Pseudomonas aeruginosa, can lead to loss of the infected eye(s) if left untreated or if allowed to reach an advanced stage before treatment is initiated. It is therefore extremely important that patients disinfect their contact lenses in accordance with the regimen prescribed by their optometrist or ophthalmologist.
Unfortunately, patients frequently fail to follow the prescribed regimens. Many patients find regimens to be difficult to understand and/or complicated, and as a result do not comply with one or more aspects of the regimen. Other patients may have a negative experience with the regimen, such as ocular discomfort attributable to the disinfecting agent, and as a result do not routinely disinfect their lenses or otherwise stray from the prescribed regimen. In either case, the risk of ocular infections is exacerbated.
Polyhexamethylenebiguanide (PHMB) is a polymeric biguanide antimicrobial agent that is widely used in solutions for disinfecting contact lenses (e.g., ReNu™ Multi-Plus Multi-Purpose Solution marketed by Bausch & Lomb, Inc.). PHMB is a strong biocide, but is known to exhibit a high degree of toxicity at elevated concentrations. It is for this reason that lens care solutions containing PHMB use it at a concentration of 0.0001% or less, so as to avoid ocular irritation in the lens wearer. However, this concentration is not sufficient to give the disinfection level desired for FDA guidelines.
The polymeric quaternary ammonium compound known as “polyquaternium-1” has also been utilized extensively in disinfecting solutions and other products utilized to treat contact lenses (referred to herein as “CLC products”). While polyquaternium-1 exhibits relatively low toxicity, it does not exhibit the required antimicrobial activity against fungi (e.g., Candida albicans) in the presence of chloride-containing salts (e.g., NaCl and other anionic components commonly contained in CLC products.
Despite the availability of various types of contact lens disinfecting systems, such as heat, hydrogen peroxide, and other chemical agents, there continues to be a need for improved systems which: 1) are simple to use, 2) have potent antimicrobial activity, and 3) are nontoxic (i.e., do not cause ocular irritation as the result of binding to the lens material).
Many pharmaceutical compositions are required to be sterile (i.e., free of bacteria, fungi and other pathogenic microorganisms). Examples of such compositions include: solutions and suspensions that are injected into the bodies of humans or other mammals; creams, lotions, solutions or other preparations that are topically applied to wounds, abrasions, burns, rashes, surgical incisions, or other conditions where the skin is not intact; and various types of compositions that are applied either directly to the eye (e.g., artificial tears, irrigating solutions, and drug products), or are applied to devices that will come into contact with the eye (e.g., contact lenses).
The foregoing types of compositions can be manufactured under sterile conditions via procedures that are well known to those skilled in the art. However, once the packaging for the product is opened, such that the composition is exposed to the atmosphere and other sources of potential microbial contamination (e.g., the hands of a human patient), the sterility of the product may be compromised. Such products are typically utilized multiple times by the patient, and are therefore frequently referred to as being of a “multi-dose” nature.
Due to the frequent, repeated exposure of multi-dose products to the risk of microbial contamination, it is necessary to employ a means for preventing such contamination from occurring. The means employed may be (1) a chemical agent that prevents the proliferation of microbes in the composition, which is referred to herein as an “antimicrobial preservative”; or (2) a packaging system that prevents or reduces the risk of microbes reaching the pharmaceutical composition within a container.
Ophthalmic compositions generally must include an anti-microbial agent to prevent contamination of the compositions by bacteria, fungi and other microbes. Such compositions may come into contact with the cornea either directly or indirectly. The cornea is particularly sensitive to exogenous chemical agents. Consequently, in order to minimize the potential for harmful effects on the cornea, it is necessary to use anti-microbial agents that are relatively non-toxic to the cornea, and to use such agents at the lowest possible concentrations (i.e., the minimum amounts required in order to perform their anti-microbial functions).
Balancing the anti-microbial efficacy and potential toxicological activity of anti-microbial agents is sometimes difficult to achieve. More specifically, the antimicrobial agent concentration necessary for the preservation of ophthalmic formulations from microbial contamination or for the disinfection of contact lenses may create the potential for toxicological effects on the cornea and/or other ophthalmic tissues. Using lower concentrations of the anti-microbial agents generally helps to reduce the potential for such toxicological effects, but the lower concentrations may be insufficient to achieve the required level of biocidal efficacy (e.g., antimicrobial preservation or disinfection).
The use of an inadequate level of antimicrobial preservation may create the potential for microbial contamination of the compositions and ophthalmic infections resulting from such contaminations. This is also a serious problem, since ophthalmic infections involving pseudomonas aeruginosa or other virulent microorganisms can lead to loss of visual function or even loss of the eye.
Thus, there is also a need for an improved means of preserving pharmaceutical compositions from microbial contamination. This need is particularly prevalent in the field of ophthalmic compositions. The antimicrobial agents utilized to preserve aqueous ophthalmic compositions must be effective in preventing microbial contamination of the compositions when used at concentrations that are non-toxic to ophthalmic tissues.
The present invention is directed to satisfying the above-cited needs.